CN100347162C - N-phenyl-2-pyrimidine-amine derivatives - Google Patents
N-phenyl-2-pyrimidine-amine derivatives Download PDFInfo
- Publication number
- CN100347162C CN100347162C CNB038035561A CN03803556A CN100347162C CN 100347162 C CN100347162 C CN 100347162C CN B038035561 A CNB038035561 A CN B038035561A CN 03803556 A CN03803556 A CN 03803556A CN 100347162 C CN100347162 C CN 100347162C
- Authority
- CN
- China
- Prior art keywords
- methyl
- compound
- nhc
- formula
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The present invention relates to novel amides and a process for preparing these amides.
Description
The invention provides new acid amides, prepare the method for these acid amides and the purposes of these acid amides.
Particularly, the invention provides new formula I acid amides or its salt or its crystallized form:
Radicals R wherein
1, R
2, R
3, R
4And R
5One of be
A) be selected from following group: low alkyl group, amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Lower alkoxy-carbonyl; With the low alkyl group of quilt amino, a low-grade alkyl amino or two elementary alkyl amido or the replacement of lower alkyl amido, or
B) unsubstituted or replace be selected from following group: benzyl amino; Benzamido; Pyrrolidyl; Piperidyl; Piperazinyl; Piperazinyl-carbonyl; Morpholinyl; Thio-morpholinyl; And by benzyl amino, benzamido, halogen, pyrrolidyl, piperidyl, piperazinyl for example 4-methyl-piperazinyl-, the low alkyl group that replaces of thio-morpholinyl or morpholinyl, the substituting group of described substituted radical is selected from cyano group; Low alkyl group; Hydroxyl-or the low alkyl group of amino-replacement; Trifluoromethyl; Free, etherificate or esterified hydroxy groups; Lower alkoxy; Lower alkanoyloxy; Free, alkylation or acidylate amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Benzamido; Free or esterifying carboxyl group; Elementary alkoxy carbonyl and halogen,
And other 4 groups are hydrogen, cyano group independently; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces; Trifluoromethyl; Free, etherificate or esterified hydroxy groups; Lower alkoxy; Lower alkanoyloxy; Free, alkylation or acidylate amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Benzamido; Free or esterifying carboxyl group; Elementary alkoxy carbonyl and halogen;
Perhaps
R
1And R
2, R
2And R
3, R
3And R
4, or R
4And R
5Be that replace or unsubstituted alkylidene group with 4 carbon atoms together, wherein substituting group preferably is selected from the low alkyl group of cyano group, unsubstituted or hydroxyl, amino or 4-methyl-piperazinyl-replacement, as particularly methyl, trifluoromethyl; Free, etherificate or esterified hydroxy groups; Free, alkylation or acidylate amino and free or esterifying carboxyl group;
And other three groups are hydrogen, cyano group independently; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces; Trifluoromethyl; Free, etherificate or esterified hydroxy groups; Lower alkoxy; Lower alkanoyloxy; Free, alkylation or acidylate amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Benzamido; Free or esterifying carboxyl group; Elementary alkoxy carbonyl and halogen;
And radicals R
6, R
7And R
8One of be halogen, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3, NHC (NH) NH
2, and other 2 groups are hydrogen, low alkyl group, rudimentary fluorinated alkyl, benzyl or phenyl independently.
The compound of formula I can be a salt form, is preferably pharmacologically acceptable salt.
This type of salt can preferably be formed such as acid salt with organic or inorganic acid by formula I that has basic nitrogen atom or IV compound, particularly pharmacologically acceptable salt.Suitable mineral acid is such as haloid acid (example hydrochloric acid), sulfuric acid or phosphoric acid.Appropriate organic is such as carboxylic acid, phosphonic acids, sulfonic acid or thionamic acid, acetic acid for example, propionic acid, sad, capric acid, laurostearic acid, oxyacetic acid, lactic acid, fumaric acid, succsinic acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, oxysuccinic acid, tartrate, citric acid, amino acid (for example L-glutamic acid or aspartic acid), toxilic acid, hydroxymaleic acid, methyl-maleic acid, the cyclohexane carboxylic acid, adamantanecarboxylic acid, phenylformic acid, oxalic acid, Whitfield's ointment, the 4-aminosallcylic acid, phthalic acid, toluylic acid, phenylglycollic acid, styracin, methane-or ethane-sulfonic acid, the 2-hydroxyethanesulfonic acid, ethane-1, the 2-disulfonic acid, Phenylsulfonic acid, the 2-naphthene sulfonic acid, 1, the 5-naphthalene disulfonic acid, 2-, 3-or 4-toluene sulfonic acide, methylsulfuric acid, ethylsulfuric acid, dodecyl sulphate, N-cyclohexyl thionamic acid, the N-methyl-, the N-ethyl-or N-propyl group thionamic acid, or other organic protonic acid, for example xitix.
For the purpose of isolated or purified, also can use not pharmacologically acceptable salt, for example picrate or perchlorate.When being used for the treatment of purposes, only use pharmacologically acceptable salt or free cpds when suitable (, be the pharmaceutical preparation form), and these are preferred.
The preferred salt of formula I is muriate, bromide, mesylate, acetate, trifluoroacetate.
Term " rudimentary " expression in the application's scope contains and is no more than and comprises 7, is preferably the group that is no more than and comprises 4 carbon atoms, is preferably methyl or ethyl.
Term " rudimentary fluorinated alkyl " expression in the application's scope contains and is no more than and comprises 7, be preferably the group that is no more than and comprises 4 carbon atoms, be preferably the methyl or the ethyl that are replaced by fluorine, they are such as one, two or three fluoro-methyl, three fluoro-ethyls.
Term " piperazinyl " the unsubstituted piperazinyl of expression in the application's scope or as 4-methyl-piperazinyl-N-low alkyl group-piperazinyl.
Halogen refers in particular to fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.
Etherified hydroxy groups is lower alkoxy preferably.Esterified hydroxy groups is preferably by such as the organic carboxyl acid of lower alkanols alkanoic acid or such as the hydroxyl of the mineral acid esterification of haloid acid, and lower alkanoyloxy or particularly halogenated for example is as iodine, bromine or particularly fluorine or chlorine.
Alkylation amino is low-grade alkyl amino for example, and for example methylamino, or two elementary alkyl amido is as dimethylamino.Acidylate amino is for example lower alkyl amido or benzamido.
The carboxyl of esterification is an elementary alkoxy carbonyl for example, as methoxycarbonyl.
R preferably
3By phenmethyl amino, benzamido, halogen, pyrrolidyl, piperidyl, piperazinyl (as 4-methyl-piperazinyl-) or the low alkyl group that replaces of morpholinyl, thio-morpholinyl, the substituting group of described substituted radical is selected from following: cyano group; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces; Trifluoromethyl; Free, etherificate or esterified hydroxy groups; Lower alkoxy; Lower alkanoyloxy; Free, alkylation or acidylate amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Benzamido; Free or esterifying carboxyl group; Elementary alkoxy carbonyl and halogen.
R preferably
3By pyrrolidyl, piperidyl, piperazinyl (as 4-methyl-piperazinyl-) or the low alkyl group that replaces of morpholinyl, thio-morpholinyl, the substituting group of described substituted radical is selected from following: low alkyl group; Hydroxyl or the amino low alkyl group that replaces;
R preferably
1, R
2, R
4, R
5And R
8Be hydrogen.
R preferably
7Be low alkyl group such as methyl or fluorinated alkyl, as trifluoromethyl.
Most preferably, R
3Be (4-methyl-piperazinyl)-methyl, R
1, R
2, R
4, R
5And R
8Be hydrogen, R
6Be halogen, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3, NHC (NH) NH
2, and R
7It is methyl.
The acid amides of formula I can prepare by method described below:
R wherein
1To R
8As top definition and R
9Be hydrogen, methyl, ethyl or aryl.
Yet non-activated carboxylic acid or ester are converted into the acid amides with amine, formula II compound for example, be difficulty and generally need high reaction temperature, as about 200 ℃, or use highly basic, as sodium methylate, sodium amide, n-Butyl Lithium, sodium hydride or Grignard reagent.Therefore need be than the more effective amidation method of method known to so far.
The application has been found that under mild conditions can successfully will try the not activating carboxy acid of II compound or the acid amides that ester is converted into formula I with the formula III compound
A) if R
9Be methyl, ethyl or aryl:
Exist
1) Lewis acid,
2) aprotic organic solvent and randomly
3) alkali,
Temperature is preferably about 40 ℃ between 20 ℃ and 80 ℃, be preferably 8 hours action time between 1 hour and 1 day, preferably under inert environments, preferably under atmospheric pressure, and the hydrolysis products therefrom; Or
B) if R
9Be hydrogen:
Exist
1) thionyl chloride,
2) aprotic organic solvent and randomly
3) alkali,
Temperature is preferably about 45 ℃ between 20 ℃ and 70 ℃, be preferably 6 hours action time between 1 hour and 1 day, preferably under inert environments, preferably under atmospheric pressure.
Therefore, the invention provides the method that is used for preparation I compound on the other hand, by formula II compound and formula III compound are reacted
A) if R
9Be methyl, ethyl or aryl:
Work as existence
1) Lewis acid,
2) aprotic organic solvent and randomly
3) alkali,
Temperature is preferably about 40 ℃ between 20 ℃ and 80 ℃, be preferably 8 hours action time between 1 hour and 1 day, preferably under inert environments, preferably under atmospheric pressure, and the hydrolysis products therefrom; Or
B) if R
9Be hydrogen:
Work as existence
4) thionyl chloride,
5) aprotic organic solvent and randomly
6) alkali,
Temperature is preferably about 45 ℃ between 20 ℃ and 70 ℃, be preferably 6 hours action time between 1 hour and 1 day, preferably under inert environments, preferably under atmospheric pressure.
Appropriate methodology A) Lewis acid comprises Al (low alkyl group) 3 (AlMe for example
3, AlEt
3, Al (iBu)
3), AlCl
3, AlBr
3, EtAlCl
2, MeAlCl
2, Me
2AlCl, Et
2AlCl and corresponding sesquichloride.Preferably, Lewis acid is selected from AlCl
3, EtAlCl
2Or Et
2AlCl, and more preferably be AlCl
3Generally, Lewis acid exists with the 1-4 molar equivalent.For AlMe
3, AlEt
3, and Al (iBu)
3, for example exist with the 2-3 molar equivalent, be preferably about 2.5 molar equivalents; For AlCl
3, AlBr
3, EtAlCl
2, MeAlCl
2, Me
2AlCl, Et
2AlCl and corresponding sesquichloride are preferably 1.5-3.5, are preferably 2.5 molar equivalents and exist.
At method B) in thionyl chloride be preferably the 1.5-10 molar equivalent, be preferably 1.5 molar equivalents.
Implementation method A) and B) aprotic organic solvent suitable the time comprises toluene/acetonitrile, toluene, benzene, chlorobenzene, dichlorobenzene, acetonitrile, 1 and pyridine.
For method A) or B) preferred alkali be N, N-diisopropylethylamine, lutidine, pyridine or tertiary amine.
On the other hand, the invention provides by with formula V compound and formula R
14The method of-H compound prepared in reaction formula I compound
Wherein,
R
13The low alkyl group that is replaced by halogen,
R
14Be benzyl amino, benzamido, pyrrolidyl, piperidyl, piperazinyl, randomly be selected from following group and replace: cyano group; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces,
R
3By the low alkyl group that benzyl amino, benzamido, pyrrolidyl, piperidyl, piperazinyl replace, described substituting group randomly is selected from following group and is replaced: cyano group; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces.
Preferably there is organic solvent in reaction, for example carries out under the condition of THF (tetrahydrofuran (THF)) or directly at amine aqueous solution R
14Carry out among-the H.
Preferably piperazinyl is a N-low alkyl group piperazine, as N methyl piperazine.
R preferably
1, R
2, R
4And R
5Be hydrogen, cyano group independently; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces; Trifluoromethyl; Free, etherificate or esterified hydroxy groups; Lower alkoxy; Lower alkanoyloxy; Free, alkylation or acidylate amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Benzamido; Free or esterifying carboxyl group; Elementary alkoxy carbonyl and halogen.
By the reaction of formula II ' compound and formula III compound can be obtained formula V compound,
Exist
1) organic solvent is as THF (tetrahydrofuran (THF))
2) alkali, as N, N-diisopropylethylamine, lutidine, pyridine or tertiary amine.
In addition, in order to react R with the formula V compound that is produced
14-H need not to be further purified and can directly join in the reaction medium.
THF can use separately or form the effectiveness of mixture with comprehensive increase solvent with other solvents.
Can form according to a conventional method and from reaction mixture the acid amides of separate type I, as from reaction mixture, removing solvent, as by the dry or almost dry acid amides that concentrates until formula I forms crystallization or precipitation is separated out such as being evaporated to; Or, go in the identical or different solvent of the solvent that uses in another kind of and the amidation step as forming salt or extracting by extracting; And the acid amides of precipitation or crystallization formula I.By routine techniques, as recrystallization or chromatography, acid amides that can purifying formula I.
Can preparation formula II or the compound of II ' by method well known to those skilled in the art.The compound of formula III can be bought from company, as Fluka, Aldrich or Acros, perhaps by method preparation well known to those skilled in the art.
Formula I compound can be used for preparation formula IV compound,
R wherein
1-R
5As mentioned above and
Radicals R
6', R
7' or R
8' one of be
R wherein
10Be the phenyl (wherein amino group is free, alkylating or acidylate in all cases) that replaces of 4-pyrazinyl, 1-methyl isophthalic acid H-pyrryl, amino or amino low alkyl group, the 1H-indyl of its five-membered ring carbon atom place keyed jointing or 1H-imidazolyl unsubstituted or low alkyl group replaces its ring carbon atom place keyed jointing and its nitrogen-atoms place is not replaced by oxygen or the pyridyl that replaced by oxygen, and R
11And R
12Be hydrogen or low alkyl group independently of each other,
And other 2 groups are hydrogen, low alkyl group independently, as methyl, phenmethyl or phenyl;
Or their pharmacologically acceptable salt or crystallized form.
Formula IV compound can exist with the form of salt, is preferably pharmacologically acceptable salt, as mentioned above.
Preferred salt is such as chlorate, Bromide, mesylate, acetate, trifluoroacetic acid.
Formula IV compound can suppress the tyrosine kinase activity of Urogastron (EGF) acceptor, and is useful, especially for the treatment of optimum or malignant tumour.They can influence tumor regression and can suppress the growth of transitivity diffusion and micro metastasis.Particularly, they can be used in treatment hyperproliferative epidermal (psoriatic), are used for the treatment of epithelium tumor, for example breast cancer and leukemia.In addition, formula IV compound also is useful for treatment by immunity system and the inflammatory reaction disease that protein kinase participates in.Formula IV compound also can be used for the treatment of by protein kinase and causes the central nervous system of the signal transmission diseases in peripheral nerve system of unifying.
Therefore, another aspect of the present invention provides the purposes that is used for formula IV compound by the method for formula I compound formula IV compound and formula I compound, wherein R
1-R
8' as described here.
The present invention relates to the method for preparation formula IV compound or pharmaceutically acceptable salt thereof or its crystallized form, by ordinary method formula I compound and the reaction of formula VII compound as described here
R wherein
10Be the phenyl (wherein amino group is free, alkylating or acidylate in all cases) that replaces of 4-pyrazinyl, 1-methyl isophthalic acid H-pyrryl, amino or amino low alkyl group, at the 1H-indyl of its five-membered ring carbon atom place keyed jointing or 1H-imidazolyl or unsubstituted or low alkyl group replaces at (as the 3-pyridyl) of its ring carbon atom place keyed jointing and its nitrogen-atoms place is not replaced by oxygen or the pyridyl that replaced by oxygen, and R
11And R
12Be hydrogen or low alkyl group and R independently of each other
11And R
12Be hydrogen or low alkyl group independently of each other.
Preferably in the first step, formula I compound is described from here formula II and III compound.
The invention still further relates to the method for preparation formula IV compound or pharmaceutically acceptable salt thereof or its crystallized form, by ordinary method with formula I compound described herein, wherein radicals R
6Be NHC (NH) NH
2,
React with formula VI compound
R wherein
10Be the phenyl (wherein amino group is free, alkylating or acidylate in all cases) that replaces of 4-pyrazinyl, 1-methyl isophthalic acid H-pyrryl, amino or amino low alkyl group, at the 1H-indyl of its five-membered ring carbon atom place keyed jointing or 1H-imidazolyl or unsubstituted or low alkyl group replaces at (as the 3-pyridyl) of its ring carbon atom place keyed jointing and its nitrogen-atoms place is not replaced by oxygen or the pyridyl that replaced by oxygen, and R
11Be hydrogen or low alkyl group.
Preferably be reflected at polar organic solvent, as carrying out in the propyl carbinol.
R preferably
10Be 3-pyridyl and R
11Be methyl.
In one embodiment, formula I compound, wherein R
6Be NHC (NH) NH
2, R
7Be methyl and R
8Be hydrogen, can be treated as formula IV compound, wherein R with for example 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone
6' be 4-(3-pyridyl)-2-pyrimdinyl-amino, R
7' be methyl and R
8' be hydrogen, corresponding to the formula IV compound described in EP 564 409 embodiment 21.Formula I compound, wherein R
6Be Br, R
7Be methyl and R
8Be hydrogen, can use such as 4-(3-pyridyl)-2-PYRIMITHAMINE and handle,, when having the phosphine part, form formula IV compound, wherein R when having Pd (0) or Pd (II) available from Chempacific
6' be 4-(3-pyridyl)-2-pyrimdinyl-amino, R
7' be methyl and R
8' be hydrogen.
In another embodiment, the standard method that utilizes the technician to know can be with formula I compound, wherein R
6Be NO
2, R
7Be methyl and R
8Be hydrogen, for example transform accepted way of doing sth I compound, wherein R
6Be NH
2, R
7Be methyl and R
8Be hydrogen.The standard method that utilizes the technician to know can be with formula I compound, wherein R
6Be halogen, NHC (O) CF
3Or NHC (O) CH
3, Br preferably, R
7Be methyl and R
8Be hydrogen, for example be converted into wherein R
6Be NH
2, R
7Be methyl and R
8It is the compound of hydrogen.Formula I compound, wherein R
6Be NH
2, R
7Be methyl and R
8Be hydrogen, can for example be converted into formula I compound, wherein R
6Be NHC (NH) NH
2, R
7Be methyl and R
8Be hydrogen.
As previously mentioned, the invention provides a kind of method of preparation formula IV compound, wherein in the first step,, preferably have AlCl from above-mentioned formula II and formula III compound formula I compound
3, Al (low alkyl group)
3, as AlMe
3, AlEt
3, Al (iBu)
3Or SOCl
2, and in second step, by ordinary method formula I compound and formula IV compound are reacted.Preferably, provide described method to be used for preparation formula IV compound, wherein R
1, R
2, R
4, R
5And R
8' be hydrogen, R
3Be (4-methyl-piperazinyl)-methyl, R
6' be 4-(3-pyridyl)-2-pyrimdinyl-amino and R
7' be methyl.
These methods of the present invention can be more effective than the method described in former document such as the EP564409 and the mode synthesis type IV compound of higher output yield, preferably R in the formula IV compound
1, R
2, R
4, R
5And R
8' be hydrogen, R
3Be (4-methyl-piperazinyl)-methyl, R
6' be 4-(3-pyridyl)-2-pyrimdinyl-amino and R
7' be methyl.Need not to use expensive coupling reagent.Output and still less the step higher than former art processes will cause significantly reduced production cost.In formerly described synthesizing, may form the intermediate of inducing mutant organism.In the method for the invention, all intermediates all show as negative (the special test of mutagenicity of AMES test; Carry out 471 according to OECD guide: bacterium reverse mutation test, ratified on July 21st, 1997 about chemical test), this is that a strong indication shows and do not form mutagenic intermediate, this will be significantly improving of occupational health.In addition, these methods allow synthesizing such as radio-labeled compound.
With by way of example method of the present invention is only described below.
AlMe
3Trimethyl aluminium is available from FLUKA
Al (iBu)
3Triisobutyl aluminium is available from FLUKA
AlCl
3Aluminum chloride is available from Merck
Platinum on the nitric sulfid is available from Acros
Thionyl chloride is available from FLUKA
Celite Filter Cel is available from FLUKA
The Rochelle salt Seignette salt is available from FLUKA
Platinum on the carbon is available from Engelhardt
Cyanamide is available from FLUKA
3-dimethylamino-1-pyridin-3-yl acrylketone is available from FLUKA
Uncle's Sodium propanecarboxylate is available from FLUKA
Rac-BINAP according to literature method synthetic 2,2 '-two-(diphenylphosphino)-1,1 '-dinaphthyl
Pd
2(dba)
3* CHCl
3Three (benzylidene-acetone)-two palladium chloroform complex bodys are available from FLUKA
Provided, especially the preferred compound to formula IV compound is N-{5-[4-(4-methyl-piperazinyl-methyl)-benzamido]-the 2-aminomethyl phenyl }-4-(3-pyridyl)-2-PYRIMITHAMINE.N-{5-[4-(4-methyl-piperazinyl-methyl)-benzamido]-the 2-aminomethyl phenyl }-4-(3-pyridyl)-2-PYRIMITHAMINE (being also referred to as " Imatinib " [INN]) and uses thereof, especially as antineoplastic agent, be described in European patent application EP-A-0 564 409 embodiment 21, this public announcement of a patent application was on October 6th, 1993, and identical application and patent are also arranged in other many countries, for example United States Patent (USP) 5,521, and 184 and Japanese Patent 2706682.The preferred compound 4-of another that provides (4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino] phenyl]-β-crystallized form of benzamide mesylate is described in european patent application 998 No. 473, is published on May 10th, 2000.
Term " 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino] phenyl]-benzamide " comprise the β-crystallized form that is described in No. 998 473, european patent application.
Most preferably be that formula IV compound is a pharmaceutical acceptable salt, in particular for single mesylate form.
Formula IV compound branch is published in patent application EP0 564 409 A1 and WO 99/03854 generically and clearly, especially in the claim of compound and in the theme of end product, the end product of work embodiment, pharmaceutical preparation, and, hereby claim is joined among the application with reference to these publications.Equally also comprise wherein disclosed corresponding steric isomer and corresponding polymorphic form, modify body as crystal.
Therefore another aspect of the present invention relates to formula I compound and is used for the synthetic purposes of formula IV compound, and wherein said formula IV compound is 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino especially] phenyl]-benzamide or its pharmacologically acceptable salt or its crystallized form.
In addition, the invention still further relates to pharmaceutical composition, it comprises
A) one or more pharmaceutically acceptable vehicle,
B) the formula IV compound of at least a pharmaceutical active and
C) weight percentage of at least a formula I compound between 0.00001% and 0.1%, most preferably is between 0.0001% and 0.1% preferably between 0.00001% and 5%.
The present invention be more particularly directed to pharmaceutical composition, especially comprise 4-(4-methylpiperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino] phenyl]-tablet of benzamide or its pharmacologically acceptable salt or its crystallized form.
C preferably) be such formula I compound or its salt, wherein R
3Be (4-methyl-piperazinyl)-methyl, R
1, R
2, R
4, R
5And R
8Be hydrogen, R
6Be Br, Cl, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3Or NHC (NH) NH
2, and R
7It is methyl.
Can there be one or more pharmaceutically acceptable vehicle in the composition, for example those usually use, as (1.1) at least a tackiness agent, as Microcrystalline Cellulose, HYDROXY PROPYL METHYLCELLULOSE, (1.2) at least a disintegrating agent, cross-linked polyvinylpyrrolidone for example, as Crospovidone , (1.3) at least a antiseize paste is as colloid silica, (1.4) at least a lubricant is as Magnesium Stearate and/or (1.5) basic dressing.According to the present invention, in tablet, use Microcrystalline Cellulose as tackiness agent.
Embodiment A: contain formula IV β-crystallized form and Imatinib (4-(4-methyl isophthalic acid-piperazine-1-ylmethyl)-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl] amino] phenyl] benzamide) capsule of mesylate
In the composition below, the 119.5mg that contains for preparing corresponding 100mg Imatinib (free alkali) names compound (=SALT I) in title as the capsule of active substance.Composition also contains following formula I compound, wherein R
3Be (4-methyl-piperazinyl)-methyl, R
1, R
2, R
4, R
5And R
8Be hydrogen, R
6Be Br, Cl, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3, NHC (NH) NH
2, and R
7It is methyl.
Composition
SALTI 119.5mg
Formula I compound 0.0005mg
Mierocrystalline cellulose MK GR 92mg
Crospovidone?XL 15mg
Aerosil?200 2mg
Magnesium Stearate 1.5mg
230.0005mg
By mixing these compositions and the hard gelatin capsule that mixture is packed into No. 1 size being prepared capsule.
Embodiment 1
The preparation of N-(4-methyl-3-bromo-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
Under argon environment 40 ℃ the time, (2M is dissolved in toluene with trimethyl aluminium solution, 15.0ml) during 30 minutes, add to 3-bromo-4-methyl-aniline (2.15g, 11.5mmol) and 4-(4-methyl-piperazine-1-ylmethyl) methyl benzoate (2.87g is in toluene 11.5mmol) (20ml) solution.After gas distributes and stops, reaction mixture was stirred 30 minutes, be cooled to 0 ℃ then, and between cold 1N NaOH (100ml) aqueous solution and toluene (100ml), distribute.With saturated NH
4The Cl aqueous solution (100ml) and the saturated NaCl aqueous solution (100ml) extracting organic layer.Concentrate the faint yellow crystallization that organic layer produces 4.69g (area of HPLC 97%) title compound in a vacuum.
Obtain 4-(4-methyl-piperazine-1-ylmethyl)-methyl benzoate as follows:
Use successively the 1-methylpiperazine (6.7g, 67mmol) and the platinum (5%) on the nitric sulfid (0.5g) handle 4-formyl-methyl benzoate (10.0g, 61mmol) solution be dissolved in methyl alcohol (100ml).Then resulting solution is heated to 90 ℃ and absorbed fully up to hydrogen with the hydrogen of 5 bar pressures processing 4 hours.Reaction mixture is cooled to room temperature and makes it filter the Celite pad.Under reduced pressure remove methyl alcohol and use toluene (100ml) to replace.With the HCl aqueous solution (2N, the resulting organic solution of 2 * 50ml) extractings.With dense NaOH solution (30%) titration aqueous phase layer to pH be 12 and (2 * 50ml) back suctions are carried with toluene.Concentrate the light yellow oil that the organic layer that merges obtains 12.9g (85%) 4-(4-methyl-piperazine-1-ylmethyl)-methyl benzoate in a vacuum, it can be further purified by under reduced pressure distilling.
Embodiment 2A
The preparation of N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
Under argon environment 45 ℃ the time, (2M is dissolved in toluene with trimethyl aluminium solution, 1.3ml, 2.6mmol) during 5 minutes, add to 3-nitro-4-methyl-aniline (152mg, 1.00mmol) and 4-(4-methyl-piperazine-1-ylmethyl) methyl benzoate (248mg is in toluene 1.00mmol) (3.0ml) solution.After gas distributes and stops, the dun reaction mixture was stirred 30 minutes, be cooled to 0 ℃ then.Add soluble tartrate saturated aqueous solution of sodium (20ml), t-butyl methyl ether (15ml) and methylene dichloride (10ml) successively.Separate organic phase also with saturated NaHCO
3The aqueous solution (10ml) and the saturated NaCl aqueous solution (10ml) washing.With t-butyl methyl ether (2 * 15ml) back suction water lift phases.Organic phase is merged, use MgSO
4Dry and the concentrated in a vacuum faint yellow crystallization that obtains 383mg (zone of HPLC 96%) title compound.
Embodiment 2B:
The preparation of N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
To the 10.95g that is dissolved in 80ml toluene (72mmol) 3-nitro-4-methyl-aniline solution during 30 minutes in 0 ℃ add 66.5ml triisobutyl aluminium (in the hexane 28%) (61mmol) in, subsequently under argon environment 0 ℃ 1 hour during, add 4-(4-methyl-piperazine-1-ylmethyl) methyl benzoate (14.9g, toluene solution 60mmol) (30ml).After the stirring at room 12 hours, (66.5ml 61mmol) adds in the dun reaction mixture with other a part of triisobutyl aluminium.After mixture continue stirred 6 hours, add then 2 extra aliquot triisobutyl aluminiums (every part of 18ml, 18mmol) and continued stirring at room several hours.After carrying out the bronsted lowry acids and bases bronsted lowry processing with sulfuric acid and NaOH respectively, the organic toluene that merges evaporates mutually in a vacuum to obtain the brown crude product, and this crude product is to crystallize out from t-butyl methyl ether to obtain being isabelline crystalline title compound: the product (11.65g) that obtains for the first time, the product (3.8g) that obtains for the second time and the product (1.2g) that obtains for the third time.Total amount 16.65g (75.3%).
Embodiment 2C:
The preparation of N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
(30.0g 0.197mol) added to tetrahydrofuran (THF) (120ml) and N-ethyl-N 23-25 ℃ the time, in the mixture of N-diisopropylamine during 5-10 minute with 4-methyl-3-nitro aniline.(38.4g 0.20mol) added in the above-mentioned solution during 60-65 minute and maintains 25-30 ℃ will to be dissolved in chloromethyl-Benzoyl chloride of tetrahydrofuran (THF) (35ml).This temperature stirred reaction mixture 30 minutes, (138.2g 1.38mol), and maintained 25-30 ℃ to add to N methyl piperazine then during 60-90 minute.Resulting suspension was stirred 60 minutes under this temperature.50 ℃ of distilled tetrahydrofurans under reduced pressure.When distillation finishes temperature transferred to 45-48 ℃ and during under this temperature 45-60 minute, add entry (300ml).Resulting suspension is cooled to 23 ℃ and stirred 60 minutes.Filter suspension, water (225ml) washing leaching cake and in a vacuum drying obtain the pale powder (HPLC 99.5% zone) of 69.2g title compound (theoretical value 95%).
In addition, resistates is added to 20-25 ℃ the time by the tetrahydrofuran (THF) of distillation half amount under reduced pressure and during 30 minutes that (300ml) can separation of intermediates N-(4-methyl-3-nitro-phenyl)-4-chloromethyl-benzamide in the water.0-5 ℃ is stirred after 30 minutes in addition, filters suspension, and water (200ml) washing is also dry in a vacuum.Intermediate is dissolved in tetrahydrofuran (THF) (150ml) and during 60-90 minute, add to N methyl piperazine (138.2g, 1,38mol), holding temperature is 25-30 ℃.Can separate title compound by above-mentioned operation.
Embodiment 3
The preparation of N-(4-methyl-3-trifluoroacetyl imidic acid (acetimidate)-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
Under argon environment 0 ℃ the time, (2M is dissolved in toluene with trimethyl aluminium solution, 1.25ml, 2.5mmol) during 5 minutes, add to 3-trifluoroacetyl imines-4-methyl-aniline (218mg, 1.00mmol) and 4-(4-methyl-piperazine-1-ylmethyl)-methyl benzoate (248mg is in toluene solution 1.00mmol) (3.0ml).After gas distributes and stops, the dun reaction mixture was stirred 3 hours for 23 ℃, be cooled to 0 ℃ then.Add soluble tartrate saturated aqueous solution of sodium (20ml) and t-butyl methyl ether (40ml) successively.Separate organic phase also with saturated NaHCO
3The aqueous solution (20ml) and the saturated NaCl aqueous solution (20ml) washing.With t-butyl methyl ether (2 * 20ml) back suction water lift phases.Organic phase is merged, use MgSO
4Dry and the concentrated in a vacuum white crystals that obtains 458mg (HPLC 94% zone) title compound.
Embodiment 4
The preparation of N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
During following 0 ℃ of argon environment, to AlCl
3(1000mg 7.5mmol) is dissolved in and drips 3-amino-4-methyl-aniline (470mg, toluene solution 6.0mmol) (6ml) in the solution of toluene (3ml) and acetonitrile (3.0ml).The gained brown solution is heated to 40 ℃.During 30 minutes, be added dropwise to 4-(4-methyl-piperazine-1-ylmethyl)-methyl benzoate (745mg, toluene solution 3.0mmol) (2ml) then.The gained mixture was stirred 8 hours at 40 ℃, be cooled to 0 ℃ then.Add Seignette salt saturated solution (30ml) and NaHCO successively
3Saturated aqueous solution (40ml) and t-butyl methyl ether (60ml).Separate organic phase also with saturated NaCl solution washing.With t-butyl methyl ether back suction water lift phase.Organic phase is merged, use MgSO
4Dry and concentrated in a vacuum.By flash chromatography method (SiO
2, CH
2Cl
2/ MeOH 90: 10+1% NH
3Water) purifying obtains the yellow crystal of 825mg title compound (75%).
Embodiment 5
The preparation of N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
With thionyl chloride (53.3g, 448mmol) during 15 minutes 0 ℃ add to 4-(4-methyl-piperazine-1-ylmethyl)-phenylformic acid (70.0g be in the toluene suspension (300ml) 299mmol).After adding end, during 45 minutes, reaction mixture is heated to 23 ℃.Under 40 ℃ of decompressions, remove excessive SOCl with the toluene condistillation
2Distillation is cooled to 0 ℃ with resulting suspension after finishing, and the filtering Benzoyl chloride, and (2 * 50ml) wash also 45 ℃ of dried overnight in a vacuum with toluene.Output: 55.0g is 79% of a theoretical value based on the amount of the dihydrochloride of Benzoyl chloride, white solid.Then exsiccant Benzoyl chloride (55g) is resuspended in toluene (100ml).During 15 minutes, dropwise add in the time of 23 ℃ 4-methyl-3-nitro aniline (22.75g, 145mmol) and pyridine (34.4g, toluene solution 435mmol) (60ml).Resulting tenne reaction mixture is heated to 45 ℃ and stirred 6 hours.Filter suspension and use toluene (300ml) and acetone (350ml) washing leaching cake successively, then filter cake is suspended from (350ml) in the water.The adding NaOH aqueous solution (30%) reaches 11 until the pH of suspension and also keeps stable.Again suspension was stirred 1 hour at 40 ℃, filter then.Water (5 * 50ml) washing leaching cakes and in a vacuum drying obtain the light brown crystallization (HPLC 98.7% zone) of 51.3g title compound (96%).
4-(4-methyl-piperazine-1-ylmethyl)-benzoic preparation:
Use successively the 1-methylpiperazine (7.3g, 73mmol) and the platinum (5%) in the nitric sulfid (1g) handle 4-formyl-phenylformic acid (10.0g, methyl alcohol 67mmol) (100ml) suspension.Then the suspension of gained is heated to 80 ℃ and make in its hydrogen environment that is in 5 crust pressure 20 hours and absorb fully until hydrogen.Reaction mixture is cooled to room temperature and makes it filter the Celite pad.Water (20ml) rinsing reactor also is dissolved in 4-(4-methyl-piperazine-1-the ylmethyl)-phenylformic acid of crystallization on wall in the reaction mixture process of cooling.The resulting aqueous solution is filtered previously used Celite pad.Concentrate the filtrate that merges in a vacuum and make it at EtOH/H
2Crystallization is to obtain 10.9g (70%) 4-(4-methyl-piperazine-1-ylmethyl)-benzoic colourless crystallization among 9: 1 v/v of O.
Embodiment 6
The preparation of N-(3-guanidine radicals-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
Similar approach with embodiment 4, there is thionyl chloride (53.3g, in the time of 448mmol), utilization is dissolved in 3-guanidine radicals-4-methyl-aniline (2.51g of toluene (300ml), 11.5mmol) and 4-(4-methyl-piperazine-1-ylmethyl)-phenylformic acid (70.0g 299mmol) obtains the greyish white colourless crystallization of 12.1g (89%) title compound.
Embodiment 7
4-dichloromethyl-N[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-preparation of benzamide:
During following 45 ℃ of argon environment, with 4-dichloromethyl-methyl benzoate (1.90g, 8.67mmol) and AlMe
3(2M is in toluene, and 12.6ml 25.2mmol) adds 4-methyl-N*3*-(4-pyridin-3-yl-pyrimidine-2-base)-benzene-1 successively, 3-diamines (2.00gmg, toluene suspension (22ml) 7.21mmol).The gained brown solution was stirred 3.5 hours for 45 ℃.Reaction mixture is cooled to 0 ℃ then, and slowly adds Rochelle salt saturated aqueous solution (70ml) quencher, thereby crude product is separated out.Successively t-butyl methyl ether (150ml) and methylene dichloride (100ml) are joined in the suspension, use NaHCO then
3Saturated aqueous solution (100ml) and NaCl saturated aqueous solution (100ml) wash.With t-butyl methyl ether (100ml) back suction water lift phase.Be contained in the crude product in the organic phase of merging with the aspirator bag filter, with t-butyl methyl ether washing and dry in a vacuum.Output: the light brown crystallization of 3.35g title compound, 84% (HPLC:91% zone) of theoretical value.
Embodiment 8
The preparation of N-(3-guanidine radicals-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
There is AlCl in similar approach with embodiment 4
3(2.0g, 15.0mmol) 40 ℃ times, utilize 3-guanidine radicals-4-methyl-aniline (1.00g, 6.09mmol) and 4-(4-methyl-piperazine-1-ylmethyl)-methyl benzoate (1.50g, 6.04mmol) solution in toluene (22ml) and acetonitrile (6ml) obtains the greyish white colourless crystallization of 1.26g (55%) title compound.
Embodiment 9
4-(4-methyl-piperazine-1-ylmethyl)-N-[4-methyl-3-(4-is than pyridine-3-base-pyrimidine-2--amino)-phenyl]-preparation of benzamide:
During following 120 ℃ of nitrogen environment, with 3-dimethylamino-1-pyridin-3-yl-acrylketone (15.3g, 87mmol) handle N-(3-guanidine radicals-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide (30g, 79mmol) suspension that is dissolved in propyl carbinol (150ml).With the gained suspension be heated to 150 ℃ 5 hours.Reaction mixture becomes the darkorange solution of homogeneous and removes dimethylamine by propyl carbinol (130ml) distillation.In still-process, add propyl carbinol (20ml).In the time of 100 ℃, dropwise add N-BUTYL ACETATE (60ml) and within an hour solution is being cooled to 0 ℃ and stirred 16 hours at 0 ℃.Filter resulting darkorange suspension with aspirator, with propyl carbinol (2 * 50ml) and water (2 * 50ml) wash isolating solids and in 60 ℃ of vacuum-dryings.Output: the canescence crystallization of 36.4g title compound, 93% (HPLC 99.6% zone) of theoretical value.
Embodiment 10
4-(4-methyl-piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidine-2--amino)-phenyl]-preparation of benzamide:
Under the argon environment, with rac-BINAP (31.2mg, 0.050mmol) and Pd
2(dba)
3* CHCl
3(13mg, 0.013mmol) mixture add to 4-(3-pyridyl)-2-PYRIMITHAMINE (172.2mg, 1.0mmol), N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide (402.4mg, 1.0mmol) and uncle's Sodium propanecarboxylate (144.2mg is in mixture 1.5mmol).Add behind the 3ml dimethylbenzene ultrasonic 10 minutes of suspension, under refluxing, stirred 5 hours then.After being cooled to room temperature, will also use methylene dichloride (each 10ml) with product extracting 4 times in water (10ml) the adding dun oil.Use MgSO
4The dry organic extraction that merges also concentrates in a vacuum.By flash chromatography method (SiO
2, methyl alcohol) and the oil of purifying brown.With product, light yellow solid is dissolved in the methylene dichloride, filters and concentrates in a vacuum.Output: 484.3mg title compound, 72% of theoretical value, (HPLC99.9% zone).Product generally comprises about 10% isomer, and this can remove by preparation property reversed phase chromatography.
Embodiment 11
The preparation of N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
Handle N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide (100g, propyl carbinol 260mmol) (1 liter) solution with the platinum (5%) on the carbon (1.0g).Then resulting suspension being heated to 70 ℃ and the hydrogen of using 0.2 crust pressure handles and to absorb fully until hydrogen in 6 hours.Reaction mixture is cooled to room temperature and filtration.Use the propyl carbinol washing catalyst.This solution is applicable to embodiment 12.Isolating product is subdued to the 3rd and is cooled to 0 ℃ and makes its crystallization (HPLC:98.0% zone).
In addition, room temperature under nitrogen environment, use platinum (5%) and potassium formiate (68.5g, 814mmol) processing N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide (60g, 90% ethanolic soln (300ml) 163mmol) on the carbon (6.0g) successively.Then the gained suspension is heated to 80 ℃ 16 hours.In the time of 70 ℃, make reaction mixture filter the Celite pad.With 90% ethanol (150ml) and water (150ml) rinsing reactor.The filtered liquid that merges by distillation in a vacuum when outside temperature is 60 ℃ is removed ethanol.Crude product can be separated from liquid concentrate as oil during the distillation, ℃ makes its crystallization and filters with aspirator at 2 hours internal cooling to 23 subsequently, with ethanol (200ml) washing and dry in a vacuum.Output: the yellow crystal of 55g title compound, 99% of theoretical value.(HPLC:98.0% zone).
Embodiment 12
The preparation of N-(3-guanidine radicals-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide:
Handle N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazine-1-ylmethyl)-benzamide (50g during successively with 85 ℃ of dense HCl solution, butanol solution 144mmol) (300ml) reaches 2.5 until pH, and (HCl 37%, 35g) and during 30 minutes with cyanamide (12.1g, 288mmol) solution-treated of water-soluble (12ml).85 ℃ of resulting reaction mixtures were stirred 20 hours the substance dissolves that begins during this period and the product of the expection formation dihydrochloride that crystallizes out from solution.(37%, 6.3g) keeping pH is 2.5 to add dense HCl in reaction process.In 1.5 hours, reaction mixture is cooled to room temperature then.Use the aspirator filtration product, (3 * 50ml) washings are also dry in a vacuum in 60 ℃ with propyl carbinol.Output: 60.7g dihydrochloride, 93% (HPLC 99% zone) of theoretical value.
In the time of 35 ℃ with dihydrochloride water-soluble (250ml).(2N 150ml) increases to 13.2 the pH of solution to add the NaOH aqueous solution.0 ℃ is separated and be cooled to the product of expection as oil from the aqueous solution makes its crystallization.0 ℃ was stirred after 1 hour, and filtration product is used K
2CO
3(5.5g/L, 2 * 50ml) washings are also dry in a vacuum in 50 ℃ for the aqueous solution.Output: the light brown crystal of 41.2g title compound is 89% of a theoretical value based on the amount of intermediate dihydrochloride, (HPLC 98.7% zone).
Claims (9)
1. the compound or its salt of following formula I:
Wherein
R
1, R
2, R
4And R
5Be hydrogen, cyano group independently; Low alkyl group; Hydroxyl or the amino low alkyl group that replaces; Trifluoromethyl; Hydroxyl; Lower alkoxy; Lower alkanoyloxy; Amino; One low-grade alkyl amino or two elementary alkyl amido; The lower alkyl amido; Benzamido; Carboxyl; Elementary alkoxy carbonyl and halogen;
R
3Be (4-methyl-piperazinyl)-methyl;
R
6Be halogen, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3Or NHC (NH) NH
2,
R
7Be methyl, and
R
8Be hydrogen;
And wherein term " rudimentary " is meant the group that has being no more than and comprise 7 carbon atoms.
2. compound according to claim 1, wherein R
6Be Br or NHC (NH) NH
2
3. compound according to claim 1, wherein R
1, R
2, R
4And R
5Be hydrogen.
4. according to the compound described in any one of the claim 1-3, wherein salt is selected from muriate, bromide, mesylate, acetate or trifluoroacetate.
5. the method for preparing the compound or its salt of following formula I:
Wherein
R
1, R
2, R
4, R
5And R
8Be hydrogen;
R
3Be (4-methyl-piperazinyl)-methyl;
R
6Be halogen, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3Or NHC (NH) NH
2, and R
7Be methyl;
Described method is with formula II compound
Amine reaction with formula III
A) R wherein
9=methyl, ethyl or aryl: exist
1) is selected from AlMe
3, AlEt
3, AliBu
3, AlCl
3, EtAlCl
2, MeAlCl
2, Me
2AlCl, Et
2The Lewis acid of AlCl or corresponding sesquichloride,
2) organic solvent, and randomly
3) alkali,
Shi Fanying, and hydrolysis products therefrom;
Perhaps
B) R wherein
9=hydrogen: exist
1) thionyl chloride,
2) organic solvent, and
3) alkali randomly,
Shi Fanying.
6. method according to claim 5, wherein A) in Lewis acid be selected from: AlMe
3, AlEt
3, AliBu
3, AlCl
3, EtAlCl
2And Et
2AlCl.
7. according to claim 5 or 6 described methods, wherein the method temperature of carrying out is 20 ℃-80 ℃.
8. the method for preparing the compound or its salt of following formula I:
Wherein
R
1, R
2, R
4, R
5And R
8Be hydrogen;
R
3Be (4-methyl-piperazinyl)-methyl;
R
6Be Br, Cl, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3Or NHC (NH) NH
2, and R
7Be methyl;
Described method is with formula V compound and formula R
14The reaction of-H compound or its salt:
Wherein,
R
1, R
2, R
4, R
5And R
8Be hydrogen;
R
6Be Br, Cl, NH
2, NO
2, NHC (O) CF
3, NHC (O) CH
3Or NHC (NH) NH
2
R
7Be methyl; And
R
13Be the methyl that is replaced by halogen,
R
14-H is a N methyl piperazine.
9. the method for preparation formula IV compound or pharmaceutically acceptable salt thereof
R wherein
1, R
2, R
4, R
5And R
8' be hydrogen; R
3Be (4-methyl-piperazinyl)-methyl; R
6' be 4-(3-pyridyl)-2-pyrimdinyl-amino; And R
7' be methyl;
Described method be in polar organic solvent by ordinary method with formula I compound
R wherein
1, R
2, R
4, R
5Be hydrogen; R
3Be (4-methyl-piperazinyl)-methyl; R
6Be NHC (NH) NH
2R
7Be methyl; And R
8Be hydrogen;
React with formula VI compound:
R wherein
10Be 3-pyridyl and R
11Be methyl.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0202873.6A GB0202873D0 (en) | 2002-02-07 | 2002-02-07 | Organic compounds |
GB0202873.6 | 2002-02-07 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2007100860099A Division CN101016262A (en) | 2002-02-07 | 2003-02-06 | N-phenyl-2-pyrimidine-amine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1630648A CN1630648A (en) | 2005-06-22 |
CN100347162C true CN100347162C (en) | 2007-11-07 |
Family
ID=9930607
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB038035561A Expired - Fee Related CN100347162C (en) | 2002-02-07 | 2003-02-06 | N-phenyl-2-pyrimidine-amine derivatives |
CNA2007100860099A Pending CN101016262A (en) | 2002-02-07 | 2003-02-06 | N-phenyl-2-pyrimidine-amine derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2007100860099A Pending CN101016262A (en) | 2002-02-07 | 2003-02-06 | N-phenyl-2-pyrimidine-amine derivatives |
Country Status (26)
Country | Link |
---|---|
US (8) | US7456283B2 (en) |
EP (2) | EP1474408B1 (en) |
JP (2) | JP4653954B2 (en) |
KR (1) | KR101027044B1 (en) |
CN (2) | CN100347162C (en) |
AU (1) | AU2003244444B2 (en) |
BR (2) | BR0307529A (en) |
CA (2) | CA2474738C (en) |
CO (1) | CO5601018A2 (en) |
CY (2) | CY1112938T1 (en) |
DK (2) | DK1474408T3 (en) |
EC (2) | ECSP045220A (en) |
ES (2) | ES2425980T3 (en) |
GB (1) | GB0202873D0 (en) |
HK (2) | HK1070893A1 (en) |
IL (3) | IL163158A (en) |
MX (1) | MXPA04007642A (en) |
NO (2) | NO327366B1 (en) |
NZ (3) | NZ534315A (en) |
PL (1) | PL209475B1 (en) |
PT (2) | PT2248807E (en) |
RU (2) | RU2370493C2 (en) |
SG (1) | SG160195A1 (en) |
SI (2) | SI2248807T1 (en) |
WO (1) | WO2003066613A1 (en) |
ZA (1) | ZA200405970B (en) |
Families Citing this family (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0202873D0 (en) | 2002-02-07 | 2002-03-27 | Novartis Ag | Organic compounds |
AU2003242988A1 (en) * | 2003-06-06 | 2005-01-04 | Adibhatla Kali Sathya Bhujanga Rao | Process for the preparation of the anti-cancer drug imatinib and its analogues |
PT1635835E (en) * | 2003-06-13 | 2010-03-17 | Novartis Ag | 2-aminopyrimidine derivatives as raf kinase inhibitors |
AR047530A1 (en) * | 2004-02-04 | 2006-01-25 | Novartis Ag | FORMS OF SALT OF 4- (4-METHYLIPIPERAZIN-1-ILMETIL) -N- (4-METHYL-3- (4-PIRIDIN-3-IL) PIRIMIDIN-2-ILAMINO) PHENYL) -BENZAMIDA |
US7507821B2 (en) | 2004-12-30 | 2009-03-24 | Chemagis Ltd. | Process for preparing Imatinib |
US8067421B2 (en) | 2006-04-27 | 2011-11-29 | Sicor Inc. | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form α |
US7977348B2 (en) | 2006-04-27 | 2011-07-12 | Sicor Inc. | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form α |
US20060223816A1 (en) * | 2006-05-08 | 2006-10-05 | Chemagis Ltd. | Imatinib mesylate alpha form and production process therefor |
BRPI0715634A2 (en) * | 2006-09-01 | 2013-07-02 | Teva Pharma | imatinib compositions |
DE602007012122D1 (en) | 2006-09-22 | 2011-03-03 | Novartis Ag | OPTIMIZATION OF THE TREATMENT OF PHILADELPHIA-POSITIVE LEUKEMIA WITH ABL-TYROSINE INHIBITOR IMATINIB |
EP1966186A1 (en) * | 2006-10-26 | 2008-09-10 | Sicor Inc. | Process for the preparation of imatinib |
EP2009008A1 (en) | 2006-10-26 | 2008-12-31 | Sicor, Inc. | Imatinib base, and imatinib mesylate and processes for preparation thereof |
RU2480461C2 (en) * | 2006-11-16 | 2013-04-27 | Ф.И.С. Фаббрика Итальяна Синтетичи С.П.А. | Method of producing imatinib and intermediate compounds thereof |
CN100451015C (en) * | 2007-02-14 | 2009-01-14 | 杭州盛美医药科技开发有限公司 | Preparing method of imatinib |
US7550591B2 (en) | 2007-05-02 | 2009-06-23 | Chemagis Ltd. | Imatinib production process |
TWI433677B (en) * | 2007-06-04 | 2014-04-11 | Avila Therapeutics Inc | Heterocyclic compounds and uses thereof |
RU2470641C2 (en) * | 2007-09-25 | 2012-12-27 | Тева Фармасьютикал Индастриес Лтд. | Stable formulations of imanitib |
EP2231161A1 (en) * | 2007-12-22 | 2010-09-29 | Synthon B.V. | A process of making imatinib |
CN101497601B (en) * | 2008-01-29 | 2012-11-07 | 福建南方制药股份有限公司 | Process for synthesizing imatinib |
PL215042B1 (en) * | 2008-08-01 | 2013-10-31 | Temapharm Spolka Z Ograniczona Odpowiedzialnoscia | Method of imatinib manufacturing |
KR20100021321A (en) * | 2008-08-14 | 2010-02-24 | 일양약품주식회사 | Process for the preparation of n-phenyl-2-pyrimidine-amine derivatives |
JP2012510470A (en) | 2008-12-01 | 2012-05-10 | ノバルティス アーゲー | A method to optimize the treatment of Philadelphia-positive leukemia with imatinib mesylate |
US20100330130A1 (en) | 2009-05-22 | 2010-12-30 | Actavis Group Ptc Ehf | Substantially pure imatinib or a pharmaceutically acceptable salt thereof |
CN101654416B (en) * | 2009-09-16 | 2013-06-05 | 成都神黄医药科技开发有限公司 | N-[3-nitro-4-methyl-phenyl]-4-aldehyde group-benzamide and preparation method thereof as well as preparation method of derivatives thereof |
WO2011070588A1 (en) | 2009-12-10 | 2011-06-16 | Arch Pharmalabs Limited | Process for the preparation of imatinib and salts thereof |
WO2011095835A1 (en) | 2010-02-02 | 2011-08-11 | Actavis Group Ptc Ehf | Highly pure imatinib or a pharmaceutically acceptable salt thereof |
WO2011130918A1 (en) * | 2010-04-23 | 2011-10-27 | 上海百灵医药科技有限公司 | Process for synthesizing imatinib |
SI2582689T1 (en) | 2010-06-18 | 2017-05-31 | Krka, D.D., Novo Mesto | New polymorphic form of imatinib base and preparation of salts thereof |
TR201007005A2 (en) | 2010-08-23 | 2011-09-21 | Mustafa Nevzat İlaç Sanayi̇i̇ A.Ş. | Imatinib base production method |
WO2013035102A1 (en) | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
RU2014120792A (en) | 2011-10-28 | 2015-12-10 | Новартис Аг | METHOD FOR TREATING STOMAL TUMORS OF THE GASTROINTESTINAL TRACT |
WO2013063003A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
WO2013120852A1 (en) | 2012-02-13 | 2013-08-22 | Grindeks, A Joint Stock Company | Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors |
KR20150036014A (en) | 2012-07-11 | 2015-04-07 | 노파르티스 아게 | Method of treating gastrointestinal stromal tumors |
CN102827144A (en) * | 2012-09-05 | 2012-12-19 | 湖南欧亚生物有限公司 | Preparation method of imatinib |
RU2537398C1 (en) * | 2013-08-20 | 2015-01-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Сибирский государственный технологический университет" (СибГТУ) | Hexasubstituted para-aminophenols with arylamide groups in 2,6 positions with respect to hydroxyl |
CN103588754B (en) * | 2013-11-04 | 2015-05-27 | 遵义医学院 | Preparation method of imatinib |
WO2018074409A1 (en) | 2016-10-17 | 2018-04-26 | Delta-Fly Pharma株式会社 | Pharmaceutical composition for treatment or remission of chronic myelogenous leukemia |
US10777331B2 (en) | 2016-11-11 | 2020-09-15 | Curium Us Llc | Processes for generating germanium-68 with reduced volatiles |
EP3333162A1 (en) | 2016-12-12 | 2018-06-13 | Silesian Catalysts sp. z o.o. | Metod for preparing n-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine |
EP3684767A1 (en) | 2017-09-22 | 2020-07-29 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
DK3697785T3 (en) | 2017-10-18 | 2023-04-03 | Jubilant Epipad LLC | IMIDAZO-PYRIDINE COMPOUNDS AS PAD INHIBITORS |
SG11202004143XA (en) | 2017-11-06 | 2020-06-29 | Jubilant Prodel LLC | Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation |
US11459338B2 (en) | 2017-11-24 | 2022-10-04 | Jubilant Episcribe Llc | Heterocyclic compounds as PRMT5 inhibitors |
CN108164505B (en) * | 2018-01-16 | 2020-11-03 | 扬州大学 | Synthesis method of imatinib |
CN111683976B (en) | 2018-02-05 | 2022-11-18 | 生物辐射实验室股份有限公司 | Chromatography resins with anion exchange-hydrophobic mixed mode ligands |
SG11202008950PA (en) | 2018-03-13 | 2020-10-29 | Jubilant Prodel LLC | Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3763234A (en) * | 1970-12-03 | 1973-10-02 | Halcon International Inc | Preparation of amides |
WO1992017066A1 (en) * | 1991-03-30 | 1992-10-15 | Bayer Aktiengesellschaft | Substituted salicylamides, agents to combat plant diseases |
CN1077713A (en) * | 1992-04-03 | 1993-10-27 | 希巴-盖吉股份公司 | Pyrimidine derivatives and preparation method thereof |
WO1996005170A1 (en) * | 1994-08-11 | 1996-02-22 | Bayer Aktiengesellschaft | 4-trifluoromethylbenzamides and their use as pesticides in plant and materials protection |
CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE531480C (en) | 1929-07-03 | 1931-08-10 | I G Farbenindustrie Akt Ges | Process for the preparation of arylides of an unsymmetrical o-xylenolcarboxylic acid |
US2808433A (en) * | 1953-08-21 | 1957-10-01 | Du Pont | Benzene dicarboxylic acid derivatives |
GB862127A (en) | 1958-07-04 | 1961-03-01 | Ici Ltd | Derivatives of 2-hydroxy-3-naphthanilide |
US3505433A (en) * | 1965-03-08 | 1970-04-07 | Hooker Chemical Corp | 2-haloperfluoro-1-cycloalken-1-ylphosphoryl compounds |
US3505389A (en) * | 1966-08-18 | 1970-04-07 | Hooker Chemical Corp | 4-amino-2,3,5,6-tetrachlorobenzoic acid and derivatives thereof |
US3505398A (en) | 1966-09-22 | 1970-04-07 | Standard Oil Co | Terephthalic acid crystallization |
JPS4987761U (en) | 1972-11-17 | 1974-07-30 | ||
JPS563375B2 (en) * | 1972-12-25 | 1981-01-24 | ||
JPS5720923B2 (en) * | 1974-04-02 | 1982-05-04 | ||
US4281000A (en) | 1979-07-09 | 1981-07-28 | American Cyanamid Company | Substituted pyrazolo (1,5-a)pyrimidines and their use as anxiolytic agents |
JPS5665804A (en) * | 1979-11-01 | 1981-06-03 | Ishihara Sangyo Kaisha Ltd | Control agent against injurious organism |
DE3305755A1 (en) * | 1983-02-19 | 1984-08-23 | Gödecke AG, 1000 Berlin | N-PHENYL-BENZAMIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN THE FIGHT AGAINST DISEASES OF THE IMMUNE SYSTEM |
US4623486A (en) | 1985-05-29 | 1986-11-18 | Pfizer Inc. | [4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity |
NZ219974A (en) * | 1986-04-22 | 1989-08-29 | Goedecke Ag | N-(2'-aminophenyl)-benzamide derivatives, process for their preparation and their use in the control of neoplastic diseases |
JP2894804B2 (en) * | 1989-07-19 | 1999-05-24 | 武田薬品工業株式会社 | 2-Amino-5-methylbenzophenones and their production |
JPH03130252U (en) | 1990-04-11 | 1991-12-27 | ||
FR2664895B1 (en) * | 1990-07-20 | 1992-10-30 | Theramex Laboratoire | NEW DERIVATIVES OF 6-METHYL 19-NOR PROGESTERONE, SUBSTITUTED IN 3 AND THEIR PROCESS FOR OBTAINING. |
US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
FR2689925B1 (en) | 1992-04-08 | 1994-05-27 | Valeo Securite Habitacle | DEVICE FOR LOCKING A LOCK IN ITS SUPPORT. |
US5543520A (en) * | 1993-10-01 | 1996-08-06 | Ciba-Geigy Corporation | Pyrimidine derivatives |
JPH0987761A (en) | 1995-09-22 | 1997-03-31 | Nikko Kinzoku Kk | Method for recovering copper from copper converter slag |
JP3130252B2 (en) | 1996-07-12 | 2001-01-31 | 小糸工業株式会社 | Seat headrest device |
ATE261443T1 (en) * | 1997-06-30 | 2004-03-15 | Targacept Inc | 3-PYRIDYL-1-AZABICYCLOALKAN DERIVATIVES FOR THE TREATMENT OF CNS DISEASES |
PT1077931E (en) * | 1998-05-15 | 2005-03-31 | Astrazeneca Ab | BEZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES |
JP2002525358A (en) | 1998-09-25 | 2002-08-13 | アストラゼネカ アクチボラグ | Benzamide derivatives and their use as cytokine inhibitors |
GB9824579D0 (en) * | 1998-11-10 | 1999-01-06 | Novartis Ag | Organic compounds |
GB9924092D0 (en) * | 1999-10-13 | 1999-12-15 | Zeneca Ltd | Pyrimidine derivatives |
GB0202873D0 (en) * | 2002-02-07 | 2002-03-27 | Novartis Ag | Organic compounds |
GB2398565A (en) * | 2003-02-18 | 2004-08-25 | Cipla Ltd | Imatinib preparation and salts |
US7338957B2 (en) * | 2003-08-28 | 2008-03-04 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
-
2002
- 2002-02-07 GB GBGB0202873.6A patent/GB0202873D0/en not_active Ceased
-
2003
- 2003-02-06 AU AU2003244444A patent/AU2003244444B2/en not_active Ceased
- 2003-02-06 CN CNB038035561A patent/CN100347162C/en not_active Expired - Fee Related
- 2003-02-06 BR BR0307529-0A patent/BR0307529A/en not_active IP Right Cessation
- 2003-02-06 KR KR1020047011670A patent/KR101027044B1/en active IP Right Grant
- 2003-02-06 SI SI200332291T patent/SI2248807T1/en unknown
- 2003-02-06 BR BRPI0307529-0A patent/BRPI0307529B1/en unknown
- 2003-02-06 CN CNA2007100860099A patent/CN101016262A/en active Pending
- 2003-02-06 CA CA2474738A patent/CA2474738C/en not_active Expired - Fee Related
- 2003-02-06 NZ NZ534315A patent/NZ534315A/en not_active IP Right Cessation
- 2003-02-06 DK DK03737319.8T patent/DK1474408T3/en active
- 2003-02-06 PT PT101713881T patent/PT2248807E/en unknown
- 2003-02-06 ES ES10171388T patent/ES2425980T3/en not_active Expired - Lifetime
- 2003-02-06 EP EP03737319A patent/EP1474408B1/en not_active Expired - Lifetime
- 2003-02-06 PL PL371197A patent/PL209475B1/en unknown
- 2003-02-06 JP JP2003565987A patent/JP4653954B2/en not_active Expired - Fee Related
- 2003-02-06 SG SG200605266-6A patent/SG160195A1/en unknown
- 2003-02-06 US US10/503,538 patent/US7456283B2/en not_active Expired - Fee Related
- 2003-02-06 EP EP10171388.1A patent/EP2248807B1/en not_active Expired - Lifetime
- 2003-02-06 DK DK10171388.1T patent/DK2248807T3/en active
- 2003-02-06 WO PCT/EP2003/001188 patent/WO2003066613A1/en active Application Filing
- 2003-02-06 NZ NZ554430A patent/NZ554430A/en not_active IP Right Cessation
- 2003-02-06 NZ NZ569731A patent/NZ569731A/en not_active IP Right Cessation
- 2003-02-06 RU RU2004126941/04A patent/RU2370493C2/en not_active IP Right Cessation
- 2003-02-06 ES ES03737319T patent/ES2384872T3/en not_active Expired - Lifetime
- 2003-02-06 CA CA2737565A patent/CA2737565C/en not_active Expired - Fee Related
- 2003-02-06 SI SI200332155T patent/SI1474408T1/en unknown
- 2003-02-06 PT PT03737319T patent/PT1474408E/en unknown
- 2003-02-06 MX MXPA04007642A patent/MXPA04007642A/en active IP Right Grant
-
2004
- 2004-07-22 IL IL163158A patent/IL163158A/en not_active IP Right Cessation
- 2004-07-27 ZA ZA200405970A patent/ZA200405970B/en unknown
- 2004-08-04 EC EC2004005220A patent/ECSP045220A/en unknown
- 2004-08-05 CO CO04076194A patent/CO5601018A2/en active IP Right Grant
- 2004-09-03 NO NO20043685A patent/NO327366B1/en not_active IP Right Cessation
-
2005
- 2005-04-28 HK HK05103664.4A patent/HK1070893A1/xx not_active IP Right Cessation
- 2005-04-28 HK HK10111709.7A patent/HK1145322A1/xx not_active IP Right Cessation
-
2007
- 2007-08-28 US US11/845,946 patent/US20070293683A1/en not_active Abandoned
- 2007-08-28 US US11/845,924 patent/US7579467B2/en not_active Expired - Fee Related
- 2007-08-28 US US11/845,914 patent/US7825247B2/en not_active Expired - Fee Related
- 2007-08-28 US US11/845,934 patent/US7816359B2/en not_active Expired - Fee Related
- 2007-12-26 RU RU2007148217/04A patent/RU2007148217A/en unknown
-
2008
- 2008-02-21 IL IL189657A patent/IL189657A/en not_active IP Right Cessation
- 2008-02-21 IL IL189658A patent/IL189658A/en not_active IP Right Cessation
-
2009
- 2009-02-02 US US12/363,838 patent/US20090137805A1/en not_active Abandoned
- 2009-05-20 NO NO20091976A patent/NO20091976L/en not_active Application Discontinuation
- 2009-07-28 EC EC2009005220A patent/ECSP095220A/en unknown
-
2010
- 2010-03-09 JP JP2010051939A patent/JP2010138194A/en active Pending
-
2012
- 2012-05-17 US US13/473,732 patent/US20120226039A1/en not_active Abandoned
- 2012-06-29 CY CY20121100584T patent/CY1112938T1/en unknown
-
2013
- 2013-08-09 CY CY20131100686T patent/CY1114351T1/en unknown
-
2014
- 2014-09-30 US US14/502,112 patent/US9573928B2/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3763234A (en) * | 1970-12-03 | 1973-10-02 | Halcon International Inc | Preparation of amides |
WO1992017066A1 (en) * | 1991-03-30 | 1992-10-15 | Bayer Aktiengesellschaft | Substituted salicylamides, agents to combat plant diseases |
CN1077713A (en) * | 1992-04-03 | 1993-10-27 | 希巴-盖吉股份公司 | Pyrimidine derivatives and preparation method thereof |
WO1996005170A1 (en) * | 1994-08-11 | 1996-02-22 | Bayer Aktiengesellschaft | 4-trifluoromethylbenzamides and their use as pesticides in plant and materials protection |
CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
Non-Patent Citations (1)
Title |
---|
A mild,genral method for conversion of esters to amides. Basha A et al.Tetrahedron letters,Vol.48 . 1977 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100347162C (en) | N-phenyl-2-pyrimidine-amine derivatives | |
CN1146415C (en) | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators | |
CN101080400A (en) | Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines | |
CN1922162A (en) | Derivatives of alkylpiperazine- and alkylhomopiperazine-carboxylates, preparation method thereof and use of same as FAAH enzyme inhibitors | |
JP6307087B2 (en) | Compounds useful for the synthesis of benzamide compounds | |
CN1805931A (en) | Process and intermediates for the preparation of (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3,1,0]hexane-2-carboxylates or salts thereof | |
CN1044816A (en) | Improvement about organic compound | |
CN1370159A (en) | Indole derivatives and their use for treatment of osteoporosis amongst other applications | |
CN1133840A (en) | Indolepiperidine derivatives | |
CN1099759A (en) | Piperazine derivatives | |
CN1423640A (en) | 8,8a-dihydro-indeno [1,2-d] thiazole derivatives, substituted in position 8a, a method for their production and their use as medicaments, e.g. anorectic agents | |
CN1109877A (en) | One-pot process for the preparation of 3-quinolone carboxylic acid derivatives | |
CN1176908C (en) | Process for producing pyridine derivate | |
CN1406234A (en) | 8,8A-dihydro-indeno [1,2-D] thiazole derivatives with a sulphonamido or sulphono substituent in the 2 position, a method for production thereof and use thereof as a medicament | |
CN1835922A (en) | Process for preparation of 4-aryl-nicotinamide derivatives | |
CN1276914C (en) | Novel cyclohexyl sulphones | |
CN1104017A (en) | Substituted (arylalkoxybenzyl) aminopropanamide derivatives, their preparation and use as anti-epileptic, neuroprotective and antidepressant agents | |
CN1105360A (en) | 1-[2H-1-benzopyran-2-one-8yl]-piperazin derivative | |
CN1232519C (en) | Method for producing 5-(1piperazinyl)-benzofuran-2-carboxamide by transition metal-catalyzed amination | |
CN1278789A (en) | 9,10-Dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors | |
KR20110086293A (en) | New preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5-yl)-n,n-dimethylacetamide | |
CN1135483A (en) | Quinoxaline and preparation method and application thereof | |
CN1533378A (en) | Process for production of quinazolines | |
CN1738808A (en) | Cyclization process for substituted benzothiazole derivatives | |
CN1138850A (en) | Novel high enantio-selective process for producing pure enantiomeric cyclopentane and cyclopentene-'beta'-amino acids |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: NOVARTIS CO., LTD. Free format text: FORMER NAME: NOVARTIS AG |
|
CP01 | Change in the name or title of a patent holder |
Address after: Basel Patentee after: Novartis Ag Address before: Basel Patentee before: Novartis AG |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071107 Termination date: 20200206 |
|
CF01 | Termination of patent right due to non-payment of annual fee |